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, Hye Yoon Chung Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University , Kangwon 25354 , Korea Search for other works by this author on: Oxford Academic Geon Seong Lee Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University , Kangwon 25354 , Korea Search for other works by this author on: Oxford Academic Soo Hyun Nam Samsung Medical Center, Cell & Gene Therapy Institute , Seoul 06351 , Korea Search for other works by this author on: Oxford Academic Jeong Hyeon Lee Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University , Kangwon 25354 , Korea Search for other works by this author on: Oxford Academic Jeong Pil Han Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University , Kangwon 25354 , Korea Search for other works by this author on: Oxford Academic Sumin Song Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University , Kangwon 25354 , Korea Search for other works by this author on: Oxford Academic Gap-Don Kim Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University , Kangwon 25354 , Korea Search for other works by this author on: Oxford Academic Choonkyun Jung Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University , Kangwon 25354 , Korea Search for other works by this author on: Oxford Academic Do Young Hyeon School of Biological Sciences, Seoul National University , Seoul 08826 , Republic of Korea Search for other works by this author on: Oxford Academic Daehee Hwang School of Biological Sciences, Seoul National University , Seoul 08826 , Republic of Korea Bioinformatics Institute, Bio-MAX, Seoul National University , Seoul 08826 , Republic of Korea Search for other works by this author on: Oxford Academic
https://orcid.org/0000-0001-5643-309X , Byung-Ok Choi Samsung Medical Center, Cell & Gene Therapy Institute , Seoul 06351 , Korea Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences & Technology , Seoul 06351 , Korea Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul 06351 , Korea Correspondence may also be addressed to: Byung-Ok Choi Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonr-ro Gangnam, Seoul 06351, Korea E-mail: bochoi77@hanmail.net Search for other works by this author on: Oxford Academic Su Cheong Yeom Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University , Kangwon 25354 , Korea Department of Agricultural Biotechnology, WCU Biomodulation Major, Seoul National University , Seoul 08826 , Korea Correspondence to: Su Cheong Yeom Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, Korea E-mail: scyeom@snu.ac.kr Search for other works by this author on: Oxford Academic
Brain, Volume 147, Issue 6, June 2024, Pages 2114–2127, https://doi.org/10.1093/brain/awae017
Published:
16 January 2024
Article history
Received:
31 July 2023
Revision received:
21 December 2023
Accepted:
09 January 2024
Published:
16 January 2024
Corrected and typeset:
16 May 2024
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Hye Yoon Chung, Geon Seong Lee, Soo Hyun Nam, Jeong Hyeon Lee, Jeong Pil Han, Sumin Song, Gap-Don Kim, Choonkyun Jung, Do Young Hyeon, Daehee Hwang, Byung-Ok Choi, Su Cheong Yeom, Morc2a variants cause hydroxyl radical-mediated neuropathy and are rescued by restoring GHKL ATPase, Brain, Volume 147, Issue 6, June 2024, Pages 2114–2127, https://doi.org/10.1093/brain/awae017
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Abstract
Mutations in the Microrchidia CW-type zinc finger 2 (MORC2) GHKL ATPase module cause a broad range of neuropathies, such as Charcot-Marie-Tooth disease type 2Z; however, the aetiology and therapeutic strategy are not fully understood. Previously, we reported that the Morc2a p.S87L mouse model exhibited neuropathy and muscular dysfunction through DNA damage accumulation.
In the present study, we analysed the gene expression of Morc2a p.S87L mice and designated the primary causing factor. We investigated the pathological pathway using Morc2a p.S87L mouse embryonic fibroblasts and human fibroblasts harbouring MORC2 p.R252W. We subsequently assessed the therapeutic effect of gene therapy administered to Morc2a p.S87L mice.
This study revealed that Morc2a p.S87L causes a protein synthesis defect, resulting in the loss of function of Morc2a and high cellular apoptosis induced by high hydroxyl radical levels. We considered the Morc2a GHKL ATPase domain as a therapeutic target because it simultaneously complements hydroxyl radical scavenging and ATPase activity. We used the adeno-associated virus (AAV)-PHP.eB serotype, which has a high CNS transduction efficiency, to express Morc2a or Morc2a GHKL ATPase domain protein in vivo. Notably, AAV gene therapy ameliorated neuropathy and muscular dysfunction with a single treatment. Loss-of-function characteristics due to protein synthesis defects in Morc2a p.S87L were also noted in human MORC2 p.S87L or p.R252W variants, indicating the correlation between mouse and human pathogenesis.
In summary, CMT2Z is known as an incurable genetic disorder, but the present study demonstrated its mechanisms and treatments based on established animal models. This study demonstrates that the Morc2a p.S87L variant causes hydroxyl radical-mediated neuropathy, which can be rescued through AAV-based gene therapy.
adeno-associated virus, Charcot-Marie-Tooth type 2Z, gene therapy, GHKL ATPase, hydroxyl radical, morc2a p.S87L
© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)
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